cGMP-independent nitric oxide signaling and regulation of the cell cycle

被引:47
作者
Cui, XL
Zhang, JH
Ma, PL
Myers, DE
Goldberg, IG
Sittler, KJ
Barb, JJ
Munson, PJ
Cintron, AD
McCoy, JP
Wang, SB
Danner, RL
机构
[1] NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA
[2] NIH, Math & Stat Comp Lab, Div Computat Biosci, Ctr Informat Technol, Bethesda, MD 20892 USA
[3] NHLBI, Flow Cytometry Core Facil, NIH, Bethesda, MD 20892 USA
[4] Mil 309th Hosp, Intens Care Unit, Beijing, Peoples R China
关键词
D O I
10.1186/1471-2164-6-151
中图分类号
Q81 [生物工程学(生物技术)]; Q93 [微生物学];
学科分类号
071005 ; 0836 ; 090102 ; 100705 ;
摘要
Background: Regulatory functions of nitric oxide (NO center dot) that bypass the second messenger cGMP are incompletely understood. Here, cGMP-independent effects of NO center dot on gene expression were globally examined in U937 cells, a human monoblastoid line that constitutively lacks soluble guanylate cyclase. Differentiated U937 cells (> 80% in G0/G1) were exposed to S-nitrosoglutathione, a NO center dot donor, or glutathione alone ( control) for 6 h without or with dibutyryl-cAMP (Bt(2)cAMP), and then harvested to extract total RNA for microarray analysis. Bt(2)cAMP was used to block signaling attributable to NO center dot-induced decreases in cAMP. Results: NO center dot regulated 110 transcripts that annotated disproportionately to the cell cycle and cell proliferation (47/110, 43%) and more frequently than expected contained AU-rich, post-transcriptional regulatory elements (ARE). Bt2cAMP regulated 106 genes; cell cycle gene enrichment did not reach significance. Like NO center dot, Bt(2)cAMP was associated with ARE-containing transcripts. A comparison of NO center dot and Bt(2)cAMP effects showed that NO center dot regulation of cell cycle genes was independent of its ability to interfere with cAMP signaling. Cell cycle genes induced by NO center dot annotated to G1/S (7/8) and included E2F1 and p21/ Waf1/Cip1; 6 of these 7 were E2F target genes involved in G1/S transition. Repressed genes were G2/M associated (24/27); 8 of 27 were known targets of p21. E2F1 mRNA and protein were increased by NO center dot, as was E2F1 binding to E2F promoter elements. NO center dot activated p38 MAPK, stabilizing p21 mRNA (an ARE-containing transcript) and increasing p21 protein; this increased protein binding to CDE/CHR promoter sites of p21 target genes, repressing key G2/M phase genes, and increasing the proportion of cells in G2/M. Conclusion: NO center dot coordinates a highly integrated program of cell cycle arrest that regulates a large number of genes, but does not require signaling through cGMP. In humans, antiproliferative effects of NO center dot may rely substantially on cGMP-independent mechanisms. Stress kinase signaling and alterations in mRNA stability appear to be major pathways by which NO center dot regulates the transcriptome.
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页数:18
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